The objective of this project is to clone and characterize up to eight genes identified by Drosophila mutants defective in synaptic transmission between photoreceptors and their target neurons. These mutants have also been shown to display specific impairments of synaptic transmission at the larval neuromuscular junction, indicating that the mutations affect basic mechanisms of synaptic transmission common in multiple classes of synapses. Because these mutants were isolated by chemical mutagenesis, however, traditional approaches to cloning the corresponding genes are tedious and time-consuming. We propose a novel approach to cloning these genes using whole-genome DNA microarrays. A major strength of this application, in addition to the use of the novel approach, is that it involves the collaborations of three investigators with complementing expertise: Dr. William L. Pak, Dr. Kendal Broadie, and Dr. Rebecca Doerge. Dr. Doerge, a statistical geneticist, will collaborate in the planning of microarrary experiments, and in the statistical analysis and interpretation of the microarray data. Dr. Pak's laboratory will have the major responsibility for carrying out the microarray experiments, and Dr. Broadie and Dr. Pak will share in the analysis of mutants. The ultimate goal of the project is to identify proteins important in synaptic transmission and characterize their functions, particularly those proteins which have homologs in mammals but whose functions have not been identified. Insofar as synapses occupy a central position in all complex neural processes, elucidation of synaptic processes are critically important in the understanding of brain functions and behavior, and hence in the understanding and management of mental illnesses. Although this work will be carried out using Drosophila because of its experimental tractability, the work is expected to lead to the identification of novel mammalian homologs and insights into their functions.